The present invention relates to biphenyl sulfonamide compounds which are combined angiotensin and endothelin receptor antagonists, to methods of using such compounds in the treatment of conditions such as hypertension and other diseases, and to pharmaceutical compositions containing such compounds.
The present invention provides biphenyl sulfonamide compounds of the following formula I, enantiomers (including atropisomers), diastereomers, salts and metabolites thereof: 
R2 is hydrogen, halogen, xe2x80x94CHO, alkyl, haloalkyl, (cycloalkyl)alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, aryloxy alkoxyalkoxy, cyano, hydroxy, hydroxyalkyl, nitro, xe2x80x94CH(OR13)(OR14), xe2x80x94(CH2)wY; with the proviso that when R1 is B, R2 is not hydrogen, halogen, alkyl, haloalkyl, alkoxy, hydroxyalkyl, nitro, xe2x80x94(CH2)wNR19R20 or xe2x80x94NHSO2R22;
R3 is heteroaryl;
R4 and R5 are each independently alkyl, hydroxyalkyl, cycloalkyl, hydroxy substituted cycloalkyl, alkoxyalkyl, or hydroxy substituted alkoxyalkyl, or R4 and R5 together form a cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or tetrahydropyranyl ring which may be optionally substituted with one or more hydroxy group;
R6 is alkyl, hydroxyalkyl, haloalkyl, hydroxy substituted haloalkyl, cycloalkyl, hydroxy substituted cycloalkyl, (cycloalkyl)alkyl, hydroxy substituted (cycloalkyl)alkyl, aralkyl, alkoxy, hydroxy substituted alkoxy, alkoxyalkyl, hydroxy substituted alkoxyalkyl, or xe2x80x94NR16R17;
R7 is xe2x80x94(CH2)wxe2x80x94CO2R15, xe2x80x94(CH2)wxe2x80x94(Cxe2x95x90O)NR16R17, xe2x80x94(CH2)wxe2x80x94NR15(Cxe2x95x90O)NR16R17, xe2x80x94(CH2)wxe2x80x94CH2OH, xe2x80x94(CH2)wxe2x80x94(Cxe2x95x90O)R15, tetrazolyl, oxadiazolyl or triazolyl wherein said tetrazolyl, oxadiazolyl or triazolyl may optionally be substituted with hydrogen, alkyl, hydroxy or halogen;
R8, R9, R9a, R10 and R12 are each independently hydrogen, halogen, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, heteroaryl, arylalkyl, alkylthioalkyl, alkoxy or alkoxyalkyl, or R9 and R9a together with the carbon atom to which they are bonded form a cycloalkyl ring;
R11 and R11a are each independently hydrogen, alkoxy, or together form a carbonyl;
R13 and R14 are alkyl or together form a five to six-membered ring;
R15, R16 and R17 are independently hydrogen, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, alkoxyalkyl, aralkyl, heterocycloalkyl, aryl, heteroaryl or xe2x80x94(CH2)wQ, or R16 and R17 may together form a four to six-membered heterocyclic ring;
n is 1 or 2;
w is 0, 1, or 2;
Y is heteroaryl, xe2x80x94COOH, xe2x80x94COOR18, xe2x80x94CONR19R20, xe2x80x94NR19R20, xe2x80x94NR19xe2x80x94OR20, xe2x80x94NR21(Cxe2x95x90O)R22, xe2x80x94NR21(Cxe2x95x90O)NR19R20, xe2x80x94N(R19)-(alk)-NR21(Cxe2x95x90O)R22, xe2x80x94NR21(Cxe2x95x90O)OR18, xe2x80x94NR21SO2R22, xe2x80x94SO2R22, Q, R or S: 
R18, R19, R20, R21 and R22 are each independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, or R19 and R20 may together form a four to seven-membered heterocyclic ring;
R23 and R24 are each independently hydrogen, alkyl or cycloalkyl, or may together form a three to seven membered cycloalkyl ring;
Z is oxygen, 
x is 2, 3 or 4;
R25, R26 and R27 are each independently hydrogen, alkyl or cycloalkyl, or R26 and R27 may together form a three to seven-membered cycloalkyl ring;
R101, R102, R103, and R104 are each independently hydrogen, halogen, xe2x80x94CHO, alkyl, haloalkyl, (cycloalkyl)alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, alkoxyalkoxy, cyano, hydroxy, hydroxyalkyl, nitro, xe2x80x94CH(OR13)(OR14), or xe2x80x94(CH2)wY; wherein said rings; aryl alone or as part of another group; or
heteroaryl alone or as part of another group may each optionally be substituted by one or more hydrogen, halogen, cyano, alkyl, hydroxyalkyl, alkoxy, nitro or trifluoromethyl groups.
The compounds of the formula I and salts thereof may be used as combined endothelin and angiotensin receptor antagonists.
Compounds of the formula I and salts thereof wherein one or more, and especially all, of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R11a, R12, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R101, R102, R103, R104, n, w, Y, Q, Z, and x are selected from the following definitions, are preferred compounds of the present invention: 
R2 is alkyl, haloalkyl, (cycloalkyl)alkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkyl, or xe2x80x94(CH2)wY, or when R1 is D, R2 is hydrogen, alkyl, haloalkyl, (cycloalkyl)alkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkyl, or (CH2)wY;
R3 is isoxazolyl, pyridizinyl, pyrazinyl or pyrimidinyl, each optionally substituted with one to three of the following substituents: hydrogen, halogen, cyano, alkyl, alkoxy, trifluoromethyl or nitro;
R4 and R5 are each independently alkyl, cycloalkyl, or R4 and R5 together form a cyclobutyl, cyclopentyl or cyclohexyl ring;
R6 is alkyl, haloalkyl, cycloalkyl or alkoxy;
R7 is xe2x80x94CO2R15, xe2x80x94(Cxe2x95x90O)NR16R17 or xe2x80x94CH2OH;
R8, R9, R10 and R12 are each independently hydrogen, halogen, alkyl, cycloalkyl, alkoxy or alkoxyalkyl;
R11 and R11a are each independently hydrogen, alkoxy, or together form a carbonyl;
R15, R16 and R17 are independently hydrogen, alkyl or cycloalkyl or R16 and R17 may together form a four to six-membered heterocyclic ring;
n is 1 or 2;
w is 0, 1, or 2;
Y is xe2x80x94COOR18, xe2x80x94NR21(Cxe2x95x90O)R22, xe2x80x94NR21(Cxe2x95x90O)NR19R20, xe2x80x94NR21(Cxe2x95x90O)OR18, xe2x80x94NR21SO2R22, xe2x80x94SO2R22 or Q;
Q is 
R18, R19, R20, R21 and R22 are each independently hydrogen, alkyl, cycloalkyl, or R19 and R20 may together form a four to seven-membered heterocyclic ring;
R23 and R24 are each independently hydrogen, alkyl or cycloalkyl, or may together form a three to seven membered cycloalkyl ring;
Z is oxygen, 
x is 2, 3 or 4;
R25, R26 and R27 are each independently hydrogen, alkyl or cycloalkyl, or R26 and R27 may together form a three to seven-membered cycloalkyl ring;
R101, R102, R103, and R104 are each independently hydrogen, halogen, alkoxy or alkyl.
Compounds of the formula I and salts thereof wherein one or more, and especially all, of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R11a, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R101, R102, R103, R104, n, w, Y, Q, Z, and x are selected from the following definitions, are more preferred compounds of the present invention: 
R2 is alkyl, haloalkyl, (cycloalkyl)alkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, hydroxyalkyl,or xe2x80x94(CH2)wY; or when R1 is D, R2 is hydrogen, alkyl, haloalkyl, (cycloalkyl)alkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkyl, or xe2x80x94(CH2)wY;
R3 is isoxazolyl, optionally substituted with one or two of the following substituents: hydrogen, halogen, cyano, alkyl, alkoxy, trifluoromethyl or nitro;
R4 and R5 are each independently alkyl, cycloalkyl, or R4 and R5 together form a cyclobutyl, cyclopentyl or cyclohexyl ring;
R6 is alkyl, haloalkyl, cycloalkyl or alkoxy;
R7 is xe2x80x94CO2R15 or xe2x80x94(Cxe2x95x90O)NR16R17;
R8, R9 and R10 are each independently hydrogen, halogen, alkyl, cycloalkyl alkoxy or alkoxyalkyl;
R11 and R11a together form a carbonyl;
R15, R16 and R17 are independently hydrogen, alkyl, or cycloalkyl or R16 and R17 may together form a four to six-membered heterocyclic ring;
n is 2;
w is 0, 1, or 2;
Y is xe2x80x94NR21(Cxe2x95x90O)R22, xe2x80x94NR21(Cxe2x95x90O)NR19R20, xe2x80x94NR21(Cxe2x95x90O)OR18, xe2x80x94NR21SO2R22, xe2x80x94SO2R22 or Q;
Q is 
R18, R19, R20, R21 and R22 are each independently hydrogen, alkyl, cycloalkyl, or R19 and R20 may together form a four to seven-membered heterocyclic ring;
R23 and R24 are each independently hydrogen, alkyl or cycloalkyl, or may together form a three to seven membered cycloalkyl ring;
Z is oxygen, 
x is 2, 3 or 4;
R25, R26 and R27 are each independently hydrogen, alkyl or cycloalkyl, or R26 and R27 may together form a three to seven-membered cycloalkyl ring;
R101, R102, R103, and R104 are each independently hydrogen, halogen, or alkyl.
Compounds of the formula I and salts thereof wherein one or more, and especially all, of R1, R2, R3, R4, R5, R6, R8, R10, R11, R11a, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R101, R102, R103, R104, w, Y, Q, Z, and x are selected from the following definitions, are most preferred compounds of the present invention: 
R2 is alkyl, haloalkyl, (cycloalkyl)alkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkyl, or xe2x80x94(CH2)wY or when R1 is D, R2 is hydrogen, alkyl, haloalkyl, (cycloalkyl)alkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkyl, or xe2x80x94(CH2)wY;
R3is isoxazol-5-yl or isoxazol-3-yl independently substituted with two of following substituents: alkyl or halogen;
R4 and R5 are each independently alkyl, cycloalkyl, or R4 and R5 together form a cyclobutyl, cyclopentyl or cyclohexyl ring;
R6 is alkyl, halo alkyl, cycloalkyl or alkoxy;
R7is xe2x80x94CO2R15 or xe2x80x94(Cxe2x95x90O)NR16R17;
R8, R9, and R10 are independently H, alkyl, cycloalkyl, alkoxy or alkoxyalkyl;
n is 2;
w is 0, 1, or 2;
Y is xe2x80x94NR21(Cxe2x95x90O)R22, xe2x80x94NR21(Cxe2x95x90O)NR19R20, xe2x80x94NR21(Cxe2x95x90O)OR18, xe2x80x94NR21SO2R22 or Q;
Q is 
R18, R19, R20, R21 and R22 are each independently hydrogen, alkyl, cycloalkyl, or R19 and R20 may together form a four to seven-membered heterocyclic ring;
R23 and R24 are each independently hydrogen, alkyl or cycloalkyl, or may together form a three to seven membered cycloalkyl ring;
Z is 
x is 2;
R25, R26 and R27 are each independently hydrogen, alkyl or cycloalkyl, or R26 and R27 may together form a three to seven-membered cycloalkyl ring;
R101, R102, R103, and R104 are each independently hydrogen, halogen, or alkyl.
Especially preferred are compounds where
R1 is selected from A, D, or E;
R2 is selected from alkyl, alkoxyalkyl, and haloalkoxyalkyl, and further selected from hydrogen when R1 is D;
R3 is isoxazol-3-yl independently substituted with two of following substituents: alkyl or halogen;
R4 and R5 together form a cyclobutyl, cyclopentyl or cyclohexyl ring;
R6 is alkyl;
R7 is xe2x80x94(Cxe2x95x90O)NR16R17;
R8, R9, and R10 are independently alkyl or alkoxy; and
R101, R102, R103, and R104 are each independently hydrogen, halogen, or alkyl.